1. Field of the Invention
The present invention relates to a novel process for the preparation of enantiomerically pure cotinine and nicotine analogs containing substituents on the pyrrolidinone/pyrrolidine ring at the 3' position of cotinine and at the 4' and 5' position of nicotine. The invention also relates to the compounds which are useful as insecticides.
2. Description of the Prior Art
Nicotine has been used as an insecticide for many years. Yamamoto has studied a number of nicotinoids (both natural and synthetic) with regard to their insecticidal activity [Agr. Biol. Chem., 26, 709 (1962); Id., 27, 445 (1963); Id., 27, 450 (1963), Id., 27, 684 (1963); Id., 32, 568 (1968); Id., 32, 747 (1968); Id., 32, 1341 (1968)]. Several of the analogs studied possessed significant toxicity towards aphids, house flies, and cockroaches. Individual enantiomers of nicotinoids have been shown to display wide differences in insecticidal activity [Richardson, C., Craig, L., and Hansberry, R., J. Econ. Entomol., 29, 850 (1936); Hansberry, R., and Norton, L., Id., 33, 734 (1940)]. For example, d-nicotine was found to be five times less effective against aphids than the natural l-nicotine. Further differences in insectidal activity between individual enantiomers and their racemic mixtures were demonstrated: the racemic mixture, d, l-nicotine, was half as potent against aphids as l-nicotine and the racemic mixture, d, l-nornicotine, was less potent against aphids than either of its enantiomeric components although the individual d- and l-nornicotine enantiomers possessed comparable toxicity against aphids. Clearly, the optical activity of a given nicotinoid is important to its biological properties and methods for the production of nicotinoids having specific optical activity are of considerable interest.
Various methods have been suggested for the chemical and biological resolution of racemic nicotine. Soeda, Y., and Yakamoto, Botyn-Kaga Ku, 34, 57 (1969); Chem. Ab. 42:6364d (abstract of article by Gol'dfarb, et al., Izvest. Akad. Nauk S.S.S.R. Otdel. Khim Nauk 1946, 557); and Yamashita, et. al., "Microbial Resolution of d,l-Nicotine", Nippon Nogei Kagaku Kaisha, Vol. 37, No. 7, pp. 385-388 (July, 1963). Other generally known methods for preparing optically pure nicotine analogs include chemical transformation of l-nicotine to yield optically pure analogs, microbial transformation of nicotine or nicotinoids to yield optically pure analogs, and chemical transformations of optically pure nicotine analogs. For example, Bowman and McKennis, "(-)-Cotinine", Biochem. Prep., 10, 35 (1963) [hereinafter cited as "Bowman and McKennis"] describes procedures for converting optically pure nicotine to optically pure cotinine.* FNT *S-cotinine is a known metabolite of S-nicotine. Morselli, et. al., J. Med. Chem., 10, pp. 1033-36 (1967).
Sanders, et. al., "Nicotine Chemistry 5'-Cyanonicotine", J. Org. Chem., 40, 19, pp. 2848-49 (1975) [hereinafter cited as "Sanders"] discloses the preparation of an inseparable mixture of (2'S)-cis-and-trans-5'-cyanonicotine from (S)-cotinine, using the method of Bowman and McKennis for the preparation of (S)-cotinine. Acid hydrolysis of the nitrile mixture and fractional crystallization produced (2'S)-cis-nicotine-5'-carboxylic acid and (2'S)-trans-nicotine-5'-carboxylic acid.
Leete, "A Systematic Degradation of Nicotine to Determine Activity at C-2' and C-5'", J. Org. Chem., 41, 21, pp. 3438-441 (1976) [hereinafter cited as "Leete"] shows preparation of (2'S)-cis and trans-5'-phenylnicotine from (5'S)-cotinine. The method disclosed comprises reacting phenyllithium with cotinine in tetrahydrofuran at -78.degree. C., acidifying the resulting mixture with HCl, and reducing the acidified mixture with NaCNBH.sub.3 or NaBH.sub.4. Reduction with NaBH.sub.4 afforded a greater proportion of the trans isomer compared to the ratio of isomers produced by NaCNBH.sub.3 reduction.
McKennis, et. al., "The Synthesis of Hydroxycotinine and Studies On Its Structure", J. Org. Chem., 28, pp. 383-85 (1963), discloses racemic 3'-acetamidocotinine and the derivatives, 3'-aminocotinine (produced by acid hydrolysis of the acetamido compound), hydroxycotinine (indicated to be 3'-hydroxycotinine, produced by diazotization of the aminocotinine), and chlorocotinine (presumed to be 3'-chlorocotinine, produced by reacting the high-melting isomer of the hydroxycotinine with thionyl chloride).
Dagne and Castagnoli, "Structure of Hydroxycotinine, a Nicotine Metabolite", J. Med. Chem., 15, 4, pp. 356-360 (1972) suggests two synthetic methods for the synthesis of cis- and trans-isomers of 3-hydroxy-1-methyl-5-(3-pyridyl)-2-pyrrolidinone. One approach described comprises hydrogenolysis of an isoxazolidine of pyridine which approach has the advantage that the reaction proceeds with retention of configuration at C-3 and C-5 of the isoxazolidine ring. Analysis of the products of both of the synthetic methods pursued established the synthetic products to be cis-3-hydroxy-1-methyl-5-(3-pyridyl)-2-pyrrolidinone and trans-3-hydroxy-1-methyl-5-(3-pyridyl)-2-pyrrolidinone. Dagne and Castagnoli also describe preparation of the corresponding mesylate (--OSO.sub.2 CH.sub.3) and acetoxy (--OCOCH.sub.3) compounds. Also see Dagne, et. al., "Deuterium Isotope Effects in the `in Vivo` Metabolism of Cotinine", J. Med. Chem., 17, 12, pp. 1330-33 (1974).
McKennis, et. al., "Demethylation of Cotinine `in Vivo`", J. Am. Chem. Soc., 81, pp. 3951-54 (1959) shows reduction of (-)-cotinine with lithium aluminum hydride in tetrahydrofuran under reflux conditions to form (-)-nicotine and prepared the acetate of impure 2'S, 4'R-4'-hydroxycotinine (obtained from the metabolism of S-cotinine by dogs) by acetylation.
Duffield, et. al., "Mass Spectrometry in Structural and Stereochemical Problems, LXXII, A Study of the Fragmentation Processes of Some Tobacco Alkaloids", J. Am. Chem. Soc., 87, 2926-932 (1965) prepared 4',4'-dibromocotinine from nicotine by bromination in a glacial acetic acid-water mixture. Heating cotinine with potassium carbonate-deuterium oxide generated cotinine-4',4'-d.sub.2. Lithium aluminum hydride reduction of this material yielded nicotine-4',4'-d.sub.2.
Overman, et. al., J. Am. Chem. Soc., 101, pp. 1310-12 (1979) describes the reaction of aldehydes and salts of 2-alkoxy-3-butenamines to form substituted 3-acylpyrrolidines, in a single step and discloses an acyl compound having the formula: ##STR2##
Tepehmbeb, et. al., Zh. Obscher Khimii, 33, 12, pp. 4006-011 (1963) discloses a compound having the formula: ##STR3##
Wasserman, et al., "Reactions of Lithium Enolates With Molecular Oxygen", Tet. Letters, 21, pp. 1731-34 (1975) describes a method for .alpha.-hydroxylation of N,N-dialkyl amides using lithium diisopropylamide to gnerate carbanions of the dialkylamide followed by rapid oxidation of the carbanion formed and reducing the resulting hydroperoxide to form the .alpha.-hydroxylated amide. The following conversion is disclosed: ##STR4##
Rueppel & Rapport, J. Am. Chem. Soc., 93, pp. 7021-28 (1971) describe the preparation of various "unnatural precursors" for the biosynthesis of nicotine analogs. A premise of the study was that it is easier to synthesize a substituted precursor and biosynthesize "unnatural" nicotine analogs than to carry out a total synthesis of an analog of a natural product. The following reaction schemes are disclosed: ##STR5## Rueppel and Rapport prepared 1,3,3-trimethyl-2-pyrrolidinone by alkylating 1-methyl-2-pyrrolidinone with 2.8 equivalents of methyl iodide in diethyl ether with lithium diisopropylamide as the base.